Interactions between polymorphic immuno-receptors and their consequences for disease susceptibility. (360G-Wellcome-074615_Z_04_A)

Interactions between polymorphic immuno-receptors and their consequences for disease susceptibility. The MHC is a gene-dense region of fundamental importance to immune defence. About 40% of expressed MHC genes are involved in immune response to infection. The region is associated with most autoimmune conditions as well as infections and other diseases. Several genes in the complex particularly class I and II are polygenic and polymorphic. These characteristics reflect their co-evolution in response to infection but may also underlie susceptibility to chronic immunostimulation, particularly where polymorphic ligands and receptors are inherited independently. We have chosen therefore to investigate interactions between variable immunoreceptors, focusing on MHC-related and linked products and their partner molecules. In addition to class I and II, that are directly involved in antigen presentation, we will study the group of MHC-linked BTN/BTL molecules, related to CD80/86 coreceptors and other family members with the B30.2 domain. We will identify conditions for induction of their expression and their ligands on dendritic cells. Other MHC-related/linked genes, of major biomedical relevance, will include class I-like RAET, TAPBP-R and TREM. We will identify genetic and functional relationships between these genes, their encoded molecules and ligands. MHC interaction with NK receptors is a key example. We will study the consequences of inheritance of different combinations of polymorphic class I and KIR on disease in humans, complemented by data from transgenics, in collaboration with other groups.